A number of different methods have been developed to perform transdermal drug delivery and/or analyte extraction, including passive diffusion of a drug or analyte between a skin patch and skin, as well as active processes such as iontophoresis, sonophoresis, electroporation, and chemically enhanced diffusion. These methods are primarily used for generating transdermal movement of small molecules, but generally do not enhance the motion of large molecules through the 10-50 micron thick outermost layer of the skin, the stratum corneum epidermidis.
PCT Publication WO 97/07734 describes thermal ablation of the stratum corneum using an electrically resistive element in contact with the stratum corneum, such that a high current through the element causes a general heating of tissue in its vicinity, most particularly the stratum corneum.
U.S. Pat. No. 5,019,034 to Weaver et al., whose disclosure is incorporated herein by reference, describes apparatus for applying high voltage, short duration electrical pulses on the skin to produce electroporation, and states that “ . . . reversible electrical breakdown . . . along with an enhanced tissue permeability, is the characteristic effect of electroporation.”
U.S. Pat. Nos. 5,885,211, 6,022,316, 6,142,939 and 6,173,202 to Eppstein et al., which are incorporated herein by reference, describe methods for forming micropores in the stratum corneum by heating tissue-bound water above the vapor point with a heat conducting element, so as to enhance transdermal transport of an analyte or active substance. Further enhancement techniques include the use of sonic energy, pressure, and chemical enhancers.
U.S. Pat. No. 5,688,233 to Hofmann et al., which is incorporated herein by reference, describes a method of transdermal molecular delivery including providing molecules to be delivered mixed with particles, contacting a selected area of a skin surface with the particles and molecules, applying a pulsed electric field of sufficient amplitude and duration to induce dielectric breakdown of the stratum corneum, and applying a pressure to the molecules to force transport of the molecules through the pores in the stratum corneum into the underlying skin.
U.S. Pat. No. 5,318,514 to Hofmann, which is incorporated herein by reference, describes an apparatus for implanting macromolecules such as genes, DNA or pharmaceuticals into a preselected surface tissue region of a patient. An applicator having a plurality of electrodes is provided for contacting a surface tissue region of a patient. A mechanism associated with the applicator delivers a predetermined quantity of a fluid medium carrying the preselected macromolecules. A signal generator is provided for generating a predetermined electric signal. The electrodes of the applicator are connected to the signal generator for applying an electric field in the surface tissue region. The field has a predetermined strength and duration in order to make the walls of a plurality of cells in the surface tissue region transiently permeable to permit the macromolecules to enter said preselected cells without damaging said cells. This technique is described as enhancing the uptake of macromolecules and thus enhancing the therapeutic effect achieved.
U.S. Pat. No. 5,462,520 to Hofmann, which is incorporated herein by reference, describes a method of transtissue molecular delivery that includes encapsulating molecules to be delivered in a microbubble carrier, contacting a selected area of a tissue surface with a solution of the encapsulated molecules, and applying an electric field of sufficient amplitude to induce electrofusion between the tissue and the membrane of the microbubble.
U.S. Pat. No. 5,464,386 to Hofmann, which is incorporated herein by reference, describes a method of transdermal molecular delivery that includes encapsulating molecules to be delivered in a vesicle, contacting a selected area of a tissue surface with a solution of the vesicles, and applying a pulsed electric field of sufficient amplitude to induce dielectric breakdown of the stratum corneum and to induce transport of the intact vesicle through the pores in the stratum corneum into the underlying tissue to enable diffusion of molecules into the tissue.
U.S. Pat. No. 3,964,482 to Gerstel, U.S. Pat. No. 6,050,988 to Zuck, and U.S. Pat. No. 6,083,196 to Trautman et al., which are incorporated herein by reference, describe other apparatus and methods for facilitating transdermal movement of a substance.
U.S. Pat. No. 6,148,232 to Avrahami, which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes apparatus for applying electrodes at respective points on skin of a subject and applying electrical energy between two or more of the electrodes to cause cell heating and subsequent ablation of the stratum corneum primarily in areas near the respective points. Various techniques for limiting ablation primarily to the stratum corneum are described, including spacing of the electrodes and monitoring the electrical resistance of skin between adjacent electrodes.
Electrosurgery is commonly used during surgical procedures today, particularly in endoscopic and laparoscopic surgery where direct access to the tissue being dissected is limited. Electrosurgery involves applying radio frequency electric current to electrodes which are used to sever tissue or achieve homeostasis. A publication entitled “Instruction Manual for the Force 2 Electrosurgical Generator” (Valleylab/Tyco Healthcare Group LP, Boulder, Colo.), which is incorporated herein by reference, describes the modes of operation of electrosurgical devices.
U.S. Pat. No. 6,159,194 to Eggers et al., which is incorporated herein by reference, describes electrosurgical apparatus and methods for inducing tissue contraction, without ablation or dissociation of surrounding tissue, in order to reduce wrinkles in skin.
U.S. Pat. Nos. 6,066,134 and 6,024,733 to Eggers et al., which are incorporated herein by reference, describe electrosurgical apparatus and methods for ablating outer layers of skin for the treatment of unwanted tissue pigmentations, melanomas, and other skin disorders.
U.S. Pat. No. 6,090,106 to Goble et al., which is incorporated herein by reference, describes monopolar and bipolar electrosurgical instruments for ablating gross tissue, such as the prostate or endometrial tissue.
U.S. Pat. No. 4,943,290 to Rexroth et al., which is incorporated herein by reference, describes electrosurgical apparatus in which a nonconductive fluid is transported to the region of an electrode in order to isolate the electrode and prevent undesirable damage of surrounding tissue.
PCT Publication WO 02/085451 to Avrahami et al., and the corresponding U.S. patent application Ser. No. 09/840,522, which are incorporated herein by reference, describe a skin treatment device that includes a plurality of electrodes, which are adapted to be placed in contact with the skin and then moved across the skin while maintaining electrical contact with the skin. The device additionally includes a power source, which is adapted to apply a current between two or more of the plurality of electrodes at the same time as the electrodes are being moved across the skin.
PCT Publication WO 02/091934 to Avrahami et al., and the corresponding U.S. patent application Ser. No. 09/859,645, which are incorporated herein by reference, describe a device for facilitating transdermal passage of a substance through skin on the body of a subject. The device preferably includes an electrode and a control unit. In a preferred embodiment, the control unit is adapted to drive the electrode to apply to the skin a current capable of ablating stratum corneum epidermidis of the skin, so as to facilitate transdermal passage of the substance. The control unit detects generation of at least one spark responsive to application of the current, and modifies a parameter of the current responsive to detecting the generation of the at least one spark.